Abstract: Autoimmunity and asthma are immune-mediated diseases, which can last for the lifetime of an individual, causing financial, physical, psychological and societal burdens. Many of these diseases are characterized by symptomatic periods or flares, followed by a time of remission. Multiple factors, such as stress and infections, are believed to be responsible for this pattern. During these diseases, T cells are persistently stimulated by self or environmental antigens. Like autoimmune diseases, exposure to pathogens, which cause a chronic infection, also results in constant T cell stimulation by persistent antigens. I have recently demonstrated that new, pathogen-specific T cells are constantly produced during the chronic phase of infection, well after the initial infectious burst has resolved. This continued thymic output was required for maintaining the immune response. As common features can pertain to different immunological situations, the hypothesis to be tested in this proposal is whether the generation of T cells specific for tissue and environmental antigens in autoimmunity and asthma during established disease is a factor responsible for perpetuation of tissue damage. This hypothesis will be tested in different models of diabetes, multiple sclerosis and a novel model of asthma. In addition, manipulation of thymic output during these chronic diseases, as well as during chronic infections, will determine whether newly developed T cells can be programmed to dampen atopic or autoimmune diseases or augment anti-microbial immunity. If successful, these studies may offer a novel explanation for the chronicity of certain immunological diseases and provide a new paradigm on which to base therapeutic intervention. Public Health Relevance: The research proposed here aims to understand how new T cells that are produced over time contribute to flares in symptoms of autoimmune diseases and asthma. This may also help us to understand why these diseases last a lifetime. Manipulation of newly produced T cells through drugs or removal of the thymus may result in a uniform treatment to interfere with multiple diseases and chronic infections.